Cellular and molecular mechanisms involved in the role of atypical neurotransmitters in neuropsychiatric disorders

• Grant number: 12/17626-7
• Support type: Research Projects - Thematic Grants
• Duration: April 01, 2013 - March 31, 2018
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Francisco Silveira Guimaraes
• Grantee: Francisco Silveira Guimaraes
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Co-Principal Investigators: Elaine Aparecida Del Bel Belluz Guimarães ; Leonardo Resstel Barbosa Moraes ; Sâmia Regiane Lourenço Joca
• Assoc. researchers: Ailton Spiacci Junior ; Alline Cristina de Campos ; Ana Carolina de Castro Issy Pereira ; Antonio de Padua Carobrez ; Daniel Gustavo dos Reis ; Daniele Cristina de Aguiar ; Elaine Aparecida Del Bel Belluz Guimarães ; Fabricio de Araujo Moreira ; Fernando Morgan de Aguiar Correa ; Frederico Rogério Ferreira ; Hélio Zangrossi Júnior ; Leandro José Bertoglio ; Leonardo Resstel Barbosa Moraes ; Mariza Bortolanza ; Plínio Cabrera Casarotto ; Rúbia Maria Monteiro Weffort de Oliveira ; Sabrina Francesca de Souza Lisboa
• Associated scholarship(s): 17/09461-1 - Investigation of the possible antipsychotic effect of HU-910, a selective type-2 cannabinoid receptor (CB2) agonist, BP.IC; 16/14282-6 - Evaluation of the cannabidiol effects under neuroimmunoendocrine and behavioral alterations induced by stress in mice, BP.DR; 15/11800-3 - The role of acute stress and mineralocorticoid and glucocorticoid receptors present in the prefrontal cortex in the memory extinction learning, BP.DR; + associated scholarships 14/22604-8 - The role or TRPV1 receptors on the modulation of aversive responses and social behavior in rodents: cellular and molecular basis of learned behavior, BP.PD; 13/07419-7 - Involvement of the dorsal hippocampus muscarinic receptors in the modulation of conditioned emotional response in rats: possible interaction with nitrergic and glutamatergic neurotransmission, BP.DR; 13/05903-9 - Effect of administration of fluoxetine and imipramine on serotonergic neurotransmission in different subregions of the dorsal raphe nucleus and dorsal periaqueductal gray of rats exposed to model Elevated T Maze, BP.DR; 13/08674-0 - Involvement of purinergic receptors in the expression, reconsolidation and extinction processes of contextual conditioned memory in mice, BP.IC; 13/13721-8 - Study of the involvement of endocannabinoid system into the prefrontal medial cortex on food intake of rats, BP.PD; 13/07470-2 - Possible involvement of TRPV1 receptors in the dorsal hippocampus in the modulation of contextual conditioned emotional response associated: a possible interaction with glutamatergic systems, nitric oxide and cGMP pathway, BP.DR; 13/03065-6 - Effects of the pharmacologic manipulation of dorsal raphe sub-regions in the modulation of defensive behaviors related to generalized anxiety and panic disorders, BP.PD; 12/18556-2 - Involvement of the glutamatergic system in the paraventricular and supra-optic nucleus on the modulation of the cardiovascular system and the vasopressin and oxytocin release, in rats submitted to osmotic stimuli, BP.PD; 11/21921-1 - The participation of the medial prefrontal cortex in reconsolidation and extinction processes of the aversive conditioned memory: possible interaction between glutamate - nitric oxide pathway and the endocanabinoids, BP.PD; 11/22523-0 - Possible neuroinflammatory mechanisms involved in the extinction deficits of conditioning fear following exposing rats to a predator: the role of endocannabinoid system, BP.PD; 09/05308-8 - Role of the hypothalamus paraventricular nucleus on cardiovascular and neuroendocrine responses observed during acute restraint stress in rats, BP.PD - associated scholarships

Abstract

In the last 15 years our group has contributed to a better understanding of the role of nitric oxide (NO) and endocannabinoids (eCBs) in physiological and pathophysiological processes of the central nervous system. We showed that manipulations of these atypical neurotransmitters are able to change behavioral and autonomic responses of laboratory animals submitted to animal models of anxiety, depression, psychosis and motor disorders. We have also shown that the phytocannabinoid cannabidiol (CBD), which, among other mechanisms, can act on eCB-mediated neurotransmission, modifies these same responses in animals and humans. The main goal of the present project, besides allowing for the continuation of this research line by approaching unresolved questions regarding NO, eCBs and CBD effects (such as unexplored sites of action, possible antiagressive and antiparkinsonin effects of CBD), is to elucidate the cellular (neuroplastic and immunological changes) and molecular (signaling pathways) mechanisms responsible for these effects. To this aim the project will try to integrate distinct methodological approaches, varying from behavioral and autonomic evaluation to measurements of gene expression, neuronal activity in specific neuronal groups, epigenetic changes, and gene silencing. As a result, in addition to increase our knowledge about these systems and the mechanisms of CBD, the Project will permit the incorporation of new and important methodological approaches to our research group. By incorporating a significant number of post-graduate students and post-docs, it will also facilitate the formation of new researchers in Neuroscience and Pharmacology. (AU)

Scientific publications

(40)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARIOTTO-DOS-SANTOS, KEILA; PADOVAN-NETO, FERNANDO EDUARDO; BORTOLANZA, MARIZA; DOS-SANTOS-PEREIRA, MAURICIO; RAISMAN-VOZARI, RITA; TUMAS, VITOR; DEL BEL, ELAINE. Repurposing an established drug: an emerging role for methylene blue in L-DOPA-induced dyskinesia. European Journal of Neuroscience, v. 49, n. 6, SI, p. 869-882, MAR 2019. Web of Science Citations: 1.

FACHIM, HELENE A.; LOUREIRO, CAMILA M.; CORSI-ZUELLI, FABIANA; SHUHAMA, ROSANA; LOUZADA, JR., PAULO; MENEZES, PAULO ROSSI; DALTON, CAROLINE F.; DEL-BEN, CRISTINA MARTA; REYNOLDS, GAVIN P. GRIN2B promoter methylation deficits in early-onset schizophrenia and its association with cognitive function. Epigenomics, v. 11, n. 4, p. 401-410, MAR 2019. Web of Science Citations: 0.

DE OLIVEIRA, RUBIA W.; OLIVEIRA, CILENE L.; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE C. Cannabinoid signalling in embryonic and adult neurogenesis: possible implications for psychiatric and neurological disorders. ACTA NEUROPSYCHIATRICA, v. 31, n. 1, p. 1-16, FEB 2019. Web of Science Citations: 1.

SALES, AMANDA J.; FOGACA, MANOELA V.; SARTIM, ARIANDRA G.; PEREIRA, VITOR S.; WEGENER, GREGERS; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L. Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Molecular Neurobiology, v. 56, n. 2, p. 1070-1081, FEB 2019. Web of Science Citations: 5.

SARTIM, ARIANDRA G.; BRITO, BIANCA M.; GOBIRA, PEDRO H.; JOCA, SAMIA R. L. Attenuation of glutamatergic and nitrergic system contributes to the antidepressant-like effect induced by capsazepine in the forced swimming test. Behavioural Pharmacology, v. 30, n. 1, p. 59-66, FEB 2019. Web of Science Citations: 0.

YAMASHITA, PAULA S. M.; ROSA, DAIANE S.; LOWRY, CHRISTOPHER A.; ZANGROSSI, JR., HELIO. Serotonin actions within the prelimbic cortex induce anxiolysis mediated by serotonin 1a receptors. JOURNAL OF PSYCHOPHARMACOLOGY, v. 33, n. 1, p. 3-11, JAN 2019. Web of Science Citations: 0.

ISSY, ANA CAROLINA; DOS-SANTOS-PEREIRA, MAURICIO; CORDEIRO PEDRAZZI, JOAO FRANCISCO; CUSSA KUBRUSLY, REGINA CELIA; DEL-BEL, ELAINE. The role of striatum and prefrontal cortex in the prevention of amphetamine-induced schizophrenia-like effects mediated by nitric oxide compounds. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 86, p. 353-362, AUG 30 2018. Web of Science Citations: 0.

LISBOA, SABRINA FRANCESCA; NIRAULA, ANZELA; RESSTEL, LEONARDO BARBOSA; GUIMARAES, FRANCISCO SILVEIRA; GODBOUT, JONATHAN P.; SHERIDAN, JOHN F. Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2. NEUROPSYCHOPHARMACOLOGY, v. 43, n. 9, p. 1924-1933, AUG 2018. Web of Science Citations: 5.

BACK, FRANKLIN P.; CAROBREZ, ANTONIO P. Periaqueductal gray glutamatergic, cannabinoid and vanilloid receptor interplay in defensive behavior and aversive memory formation. Neuropharmacology, v. 135, p. 399-411, JUN 2018. Web of Science Citations: 2.

FOGACA, MANOELA V.; CAMPOS, ALLINE C.; COELHO, LUDMILA D.; DUMAN, RONALD S.; GUIMARAES, FRANCISCO S. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology, v. 135, p. 22-33, JUN 2018. Web of Science Citations: 8.

STANQUINI, LAURA ALVES; BIOJONE, CAROLINE; GUIMARAES, FRANCISCO SILVEIRA; JOCA, SAMIA REGIANE. Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression. ACTA NEUROPSYCHIATRICA, v. 30, n. 3, p. 127-136, JUN 2018. Web of Science Citations: 0.

SPIACCI, JR., AILTON; VILELA-COSTA, HELOISA H.; SANT'ANA, ANA BEATRIZ; FERNANDES, GABRIEL GRIPP; FRIAS, ALANA TERCINO; FERREIRA DA SILVA, GLAUBER S.; ANTUNES-RODRIGUES, JOSE; ZANGROSSI, JR., HELIO. Panic-like escape response elicited in mice by exposure to CO2, but not hypoxia. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 81, p. 178-186, FEB 2 2018. Web of Science Citations: 3.

SCARANTE, FRANCIELE F.; VILA-VERDE, CARLA; DETONI, VINICIUS L.; FERREIRA-JUNIOR, NILSON C.; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE C. Cannabinoid Modulation of the Stressed Hippocampus. FRONTIERS IN MOLECULAR NEUROSCIENCE, v. 10, DEC 19 2017. Web of Science Citations: 5.

SILVA, NICOLE R.; GOMES, FELIPE V.; FONSECA, MIRIAM D.; MECHOULAM, RAPHAEL; BREUER, AVIVA; CUNHA, THIAGO M.; GUIMARAES, FRANCISCO S. Antinociceptive effects of HUF-101, a fluorinated cannabidiol derivative. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 79, n. B, p. 369-377, OCT 3 2017. Web of Science Citations: 3.

STERN, CRISTINA A. J.; DA SILVA, THIAGO R.; RAYMUNDI, ANA M.; DE SOUZA, CAMILA P.; HIROAKI-SATO, VINICIUS A.; KATO, LUIZA; GUIMARAES, FRANCISCO S.; ANDREATINI, ROBERTO; TAKAHASHI, REINALDO N.; BERTOGLIO, LEANDRO J. Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors. Neuropharmacology, v. 125, p. 220-230, OCT 2017. Web of Science Citations: 13.

ALMEIDA-SANTOS, ANA F.; MOREIRA, FABRICIO A.; GUIMARAES, FRANCISCO S.; AGUIAR, DANIELE C. 2-Arachidonoylglycerol endocannabinoid signaling coupled to metabotropic glutamate receptor type-5 modulates anxiety-like behavior in the rat ventromedial prefrontal cortex. JOURNAL OF PSYCHOPHARMACOLOGY, v. 31, n. 6, p. 740-749, JUN 2017. Web of Science Citations: 1.

SARTIM, A. G.; MOREIRA, F. A.; JOCA, S. R. L. INVOLVEMENT OF CB1 AND TRPV1 RECEPTORS LOCATED IN THE VENTRAL MEDIAL PREFRONTAL CORTEX IN THE MODULATION OF STRESS COPING BEHAVIOR. Neuroscience, v. 340, p. 126-134, JAN 6 2017. Web of Science Citations: 6.

CARTA, ANNA R.; MULAS, GIOVANNA; BORTOLANZA, MARIZA; DUARTE, TERENCE; PILLAI, ELISABETTA; FISONE, GILBERTO; VOZARI, RITA RAISMAN; DEL-BEL, ELAINE. L-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role?. European Journal of Neuroscience, v. 45, n. 1, p. 73-91, JAN 2017. Web of Science Citations: 0.

CARTA, ANNA R.; MULAS, GIOVANNA; BORTOLANZA, MARIZA; DUARTE, TERENCE; PILLAI, ELISABETTA; FISONE, GILBERTO; VOZARI, RITA RAISMAN; DEL-BEL, ELAINE. l-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role?. European Journal of Neuroscience, v. 45, n. 1, SI, p. 73-91, JAN 2017. Web of Science Citations: 9.

DOS-SANTOS-PEREIRA, MAURICIO; DA-SILVA, CELIA APARECIDA; GUIMARAES, FRANCISCO SILVEIRA; DEL-BEL, ELAINE. Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: Possible mechanism of action. Neurobiology of Disease, v. 94, p. 179-195, OCT 2016. Web of Science Citations: 14.

SPIACCI, JR., AILTON; HENSCHEL POBBE, ROGER LUIS; MATTHIESEN, MELINA; ZANGROSSI, JR., HELIO. 5-HT1A receptors of the rat dorsal raphe lateral wings and dorsomedial subnuclei differentially control anxiety- and panic-related defensive responses. Neuropharmacology, v. 107, p. 471-479, AUG 2016. Web of Science Citations: 7.

FOGACA, M. V.; FEDOCE, A. G.; FERREIRA-JUNIOR, N. C.; GUIMARES, F. S.; RESSTEL, L. B. Involvement of M1 and CB1 receptors in the anxiogenic-like effects induced by neostigmine injected into the rat prelimbic medial prefrontal cortex. Psychopharmacology, v. 233, n. 8, p. 1377-1385, APR 2016. Web of Science Citations: 2.

SALES, AMANDA JULIANA; LOURENCO JOCA, SAMIA REGIANE. Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels. ACTA NEUROPSYCHIATRICA, v. 28, n. 1, p. 11-22, FEB 2016. Web of Science Citations: 16.

FEDOCE, A. G.; FERREIRA-JUNIOR, N. C.; REIS, D. G.; CORREA, F. M. A.; RESSTEL, L. B. M. M-3 muscarinic receptor in the ventral medial prefrontal cortex modulating the expression of contextual fear conditioning in rats. Psychopharmacology, v. 233, n. 2, p. 267-280, JAN 2016. Web of Science Citations: 4.

GOBIRA, P. H.; ALMEIDA-SANTOS, A. F.; GUIMARAES, F. S.; MOREIRA, F. A.; AGUIAR, D. C. Role of the endocannabinoid 2-arachidonoylglycerol in aversive responses mediated by the dorsolateral periaqueductal grey. European Neuropsychopharmacology, v. 26, n. 1, p. 15-22, JAN 2016. Web of Science Citations: 7.

BATISTA, PRISCILA A.; FOGACA, MANOELA V.; GUIMARAES, FRANCISCO S. The endocannabinoid, endovanilloid and nitrergic systems could interact in the rat dorsolateral periaqueductal gray matter to control anxiety-like behaviors. Behavioural Brain Research, v. 293, p. 182-188, OCT 15 2015. Web of Science Citations: 7.

LISBOA, SABRINA F.; BORGES, ANNA A.; NEJO, PRISCILA; FASSINI, ALINE; GUIMARAES, FRANCISCO S.; RESSTEL, LEONARDO B. Cannabinoid CBI receptors in the dorsal hippocampus and prelimbic medial prefrontal cortex modulate anxiety-like behavior in rats: Additional evidence. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 59, p. 76-83, JUN 3 2015. Web of Science Citations: 9.

FASSINI, ALINE; ANTERO, LEANDRO S.; CORREA, FERNANDO M. A.; JOCA, SAMIA R.; RESSTEL, LEONARDO B. M. The Prelimbic Cortex Muscarinic M-3 Receptor-Nitric Oxide-Guanylyl Cyclase Pathway Modulates Cardiovascular Responses in Rats. Journal of Neuroscience Research, v. 93, n. 5, p. 830-838, MAY 2015. Web of Science Citations: 3.

GOMES, FELIPE V.; LLORENTE, RICARDO; DEL BEL, ELAINE A.; VIVEROS, MARIA-PAZ; LOPEZ-GALLARDO, MERITXELL; GUIMARAES, FRANCISCO S. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. SCHIZOPHRENIA RESEARCH, v. 164, n. 1-3, p. 155-163, MAY 2015. Web of Science Citations: 38.

VIANA, THERCIA G.; HOTT, SARA C.; RESSTEL, LEONARDO B.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A. Anti-aversive role of the endocannabinoid system in the periaqueductal gray stimulation model of panic attacks in rats. Psychopharmacology, v. 232, n. 9, p. 1545-1553, MAY 2015. Web of Science Citations: 10.

AGUIAR, DANIELE C.; ALMEIDA-SANTOS, ANA F.; MOREIRA, FABRICIO A.; GUIMARAES, FRANCISCO S. Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses. ACTA NEUROPSYCHIATRICA, v. 27, n. 2, p. 97-105, APR 2015. Web of Science Citations: 3.

FASSINI, ALINE; SCOPINHO, AMERICA A.; RESSTEL, LEONARDO B. M.; CORREA, FERNANDO M. A. kappa-Opioid receptors in the infralimbic cortex modulate the cardiovascular responses to acute stress. Experimental Physiology, v. 100, n. 4, p. 377-387, APR 2015. Web of Science Citations: 4.

FOGACA, MANOELA V.; SONEGO, ANDREZA B.; RIOLI, VANESSA; GOZZO, FABIO C.; DALE, CAMILA S.; FERRO, EMER S.; GUIMARAES, FRANCISCO S. Anxiogenic-like effects induced by hemopressin in rats. Pharmacology Biochemistry and Behavior, v. 129, p. 7-13, FEB 2015. Web of Science Citations: 14.

AGUIAR, D. C.; MOREIRA, F. A.; TERZIAN, A. L.; FOGACA, M. V.; LISBOA, S. F.; WOTJAK, C. T.; GUIMARAES, F. S. Modulation of defensive behavior by Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channels. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 46, n. 3, SI, p. 418-428, OCT 2014. Web of Science Citations: 24.

FASSINI, ALINE; SCOPINHO, AMERICA A.; RESSTEL, LEONARDO B. M.; CORREA, FERNANDO M. A. Opioid receptors in the prelimbic cortex modulate restraint stress-induced cardiovascular responses in the rat. Neuropharmacology, v. 85, p. 367-374, OCT 2014. Web of Science Citations: 6.

LISBOA, S. F.; CAMARGO, L. H. A.; MAGESTO, A. C.; RESSTEL, L. B. M.; GUIMARAES, F. S. Cannabinoid modulation of predator fear: involvement of the dorsolateral periaqueductal gray. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 17, n. 8, p. 1193-1206, AUG 2014. Web of Science Citations: 7.

FOGACA, M. V.; REIS, F. M. C. V.; CAMPOS, A. C.; GUIMARAES, F. S. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: Involvement of 5HT(1A) receptors and previous stressful experience. European Neuropsychopharmacology, v. 24, n. 3, p. 410-419, MAR 2014. Web of Science Citations: 43.

MORAES-NETO, T. B.; SCOPINHO, A. A.; BIOJONE, C.; CORREA, F. M. A.; RESSTEL, L. B. M. INVOLVEMENT OF DORSAL HIPPOCAMPUS GLUTAMATERGIC AND NITRERGIC NEUROTRANSMISSION IN AUTONOMIC RESPONSES EVOKED BY ACUTE RESTRAINT STRESS IN RATS. Neuroscience, v. 258, p. 364-373, JAN 31 2014. Web of Science Citations: 14.

TRISTAO, FABRINE S. M.; AMAR, MAJID; LATROUS, INES; DEL-BEL, ELAINE A.; PREDIGER, RUI D.; RAISMAN-VOZARI, RITA. Evaluation of Nigrostriatal Neurodegeneration and Neuroinflammation Following Repeated Intranasal 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Administration in Mice, an Experimental Model of Parkinson's Disease. NEUROTOXICITY RESEARCH, v. 25, n. 1, p. 24-32, JAN 2014. Web of Science Citations: 13.

ALMEIDA-SANTOS, A. F.; GOBIRA, P. H.; ROSA, L. C.; GUIMARAES, F. S.; MOREIRA, F. A.; AGUIAR, D. C. Modulation of anxiety-like behavior by the endocannabinoid 2-arachidonoylglycerol (2-AG) in the dorsolateral periaqueductal gray. Behavioural Brain Research, v. 252, p. 10-17, SEP 1 2013. Web of Science Citations: 21.